Generalized vitiligo is the most common pigmentation disorder, in which white patches of skin and overlying hair result from autoimmune loss of melanocytes from the affected areas. Generalized vitiligo has complex and heterogeneous etiology, with strong evidence for both genetic and environmental causal factors. Genome-wide linkage studies using multiplex families have provided evidence that several chromosomal regions contribute to risk of generalized vitiligo, although specific regions and genes involved may differ among patients of European Caucasian (CEU) versus Asian ethnic origin, and several genes have yielded repeated, though not perfectly consistent, evidence of association from case-control or family-based studies (rev. in Spritz, 2007, 2008). Discovery of underlying genetic components of vitiligo is key to understanding disease pathogenesis, with the long-term goal of developing treatments that suppress or re-regulate autoimmunity, thereby enhancing treatments that stimulate skin re-pigmentation by melanocyte re-population. Our previous grant cycle was aimed at genetic linkage analysis of generalized vitiligo, with the specific aims of collecting samples from multiplex families, carrying out extension and replication linkage analysis of genotype data from these and previously collected families, and identifying the gene corresponding to AIS1, which we had mapped to chromosome 1p. All of those goals were achieved, as well as identification of SLEV1 on 17p and mapping of several additional linkage signals on other chromosomes. This is a 3-year application that builds on our progress. Aim 1 is to carry out functional studies of a vitiligo susceptibility gene we've already identified, NALP1. Aim 2 is to carry out additional genetic studies to replicate candidate linkage/association signals we've previously detected on chromosomes 7 and 9, and to identify the causal genes, with eventual functional studies planned for once those genes are identified. Aim 3 is to map and identify an apparent recessive vitiligo susceptibility locus by taking advantage of a special founder population;the opportunity to detect locus-specific recessive disease susceptibility loci may well be essentially impossible by any other approach. The work proposed here parallels, and takes advantage of a genomewide association study (GWAS) of generalized vitiligo that will be carried out by the Principal Investigator, and provides value-added to the GWAS by using the GWAS data in Aim 3 to identify a recessive vitiligo susceptibility gene that almost certainly could not be identified by the GWAS itself. Further, the GWAS project includes no functional studies. This grant application thus does not overlap the GWAS, and instead will yield information that is complementary. PUBLIC HEALTH RELEVANCE: Generalized vitiligo is the most common pigmentation disorder, autoimmune death of melanocytes resulting in white patches of skin and hair, and patients are at high risk of other autoimmune diseases such as thyroid disease, adult type 1 diabetes, rheumatoid arthritis, lupus, and others. Generalized vitiligo involves both genes and environmental triggers. The current studies aim to follow-up functional consequences of a vitiligo susceptibility gene identified in previous grant years (NALP1), to identify new vitiligo susceptibility genes in regions of genetic linkage identified in previous grant years (chromosome 7, chromosome 9), and to identify a novel vitiligo susceptibility gene in an inbred "founder population" from Romania.